DESCRIPTION: (Applicant's Abstract) The long-term goals of this research are an understanding of neurobehavioral mechanisms determining the addictive liabilities of drugs and the rational development of pharmacotherapies that will act on these mechanisms to reduce or eliminate addictive behavior. Recent research in this laboratory has focused on the neuropharmacology of iboga alkaloids (e.g., ibogaine) and congeners (e.g., 18-methoxycoronaridine) and their interactions with opioid and stimulant drugs of abuse. The methodology uses rats and involves measurement of intravenous drug self-administration and of drug effects on brain chemistry. In vivo microdialysis combined with HPLC (high performance liquid chromatography) is used to assay extracellular levels of biogenic amines (dopamine, serotonin) and their metabolites in discrete brain regions. Specific aims include the following: (1) The effects of ibogaine, its metabolite noribogaine and two iboga alkaloid congeners [18-methoxycoronaridine and 18-(N,N-dimethylaminoethyl)-coronaridine] on morphine and cocaine self-administration will continue to be investigated; it should be possible to develop agents that are at least as potent as ibogaine in suppressing drug self-administration but are much safer; iboga agents will be assessed on acquisition and on ongoing rates of drug self-administration behavior, in two models of relapse, and in a new oral model of nicotine preference. (2) Neurochemical mechanisms that might mediate putative anti-addictive effects of the same four iboga agents will be studied. In vivo microdialysis will be used to characterize the neurochemical actions of iboga agents and to define the receptor mechanisms mediating these effects; microdialysis will also be performed in rats self-administering morphine or cocaine in order to correlate neurochemical and behavioral effects of specific treatments. It is hypothesized that the unique pharmacology of these agents derives from a combination of actions at kappa opioid and NMDA receptors and at serotonin uptake sites. (3) Using GCMS (gas chromatography-mass spectrometry), the distribution and metabolism of the iboga agents will be studied. It is hypothesized that long-term effects of these agents are mediated by persistent low levels of the parent compounds and/or by active metabolites in discrete brain regions. This research may result in novel treatments for addictive disorders in humans.